Insulin receptor substrate (IRS)-1 is a key protein in insulin signaling. Several studies have shown that the expression of IRS-1 can be modulated by protein degradation via the proteasome and the degradation of IRS-1 can be related to insulin-resistant states. The degradation of IRS-1 has been shown to be induced by SOCS-1 and SOCS-3 via the ubiquitin pathway. The goal Of Our study was to determine if the induction of SOCS-3 correlated with increased IRS-1 degradation in cultured 3T3-L1 adipocytes. Interestingly, our studies have shown that there is little correlation between the induction in SOCS-3 expression and the degradation of IRS-1 in mature 3T3-L1 adipocytes. Our results clearly demonstrate that treatment with leukemia inhibitory factor(LIF) or cardiotrophin (CT)-1 strongly induces the expression of SOCS-3 in mature 3T3-L1 adipocytes, but does not affect the degradation of IRS-1. On the contrary, tumor necrosis factor(TNF) alpha and insulin, which very weakly induce SOCS-3 expression, have profound effects on IRS-1 degradation. In summary, our results indicate that the expression of SOCS-3 does not correlate with the degradation of IRS-1 proteins in fat cells. (c) 2006 Elsevier Inc. All rights reserved.